TY - JOUR
AU1 - Kojro,, Grzegorz
AU2 - Wroczyński,, Piotr
AB - Abstract Cloud point extraction (CPE) is a simple, safe and environment-friendly technique used in the preparation of various samples. It was primarily developed for the assessment of environmental samples, especially analyzed for metals. Recently, this technique has been used in the extraction and determination of various chemical compounds (e.g., drugs, pesticides and vitamins), in various matrices (e.g., human plasma, human serum, milk and urine). In this review, we show that CPE is a reliable method of extraction and can be used in analytical laboratories in combination with other techniques that can be used in the determination of drugs and other chemicals in the human biological matrix. According to the literature, a combination of different methods provides good recovery and can be used in the simultaneous determination of many drugs in a single analysis. CPE can be optimized by changing its conditions (e.g., type of surfactant used, incubation temperature, pH and the addition of salts). In this review, we present the optimized CPE methods used in the determination of various pharmaceuticals and describe how the conditions affect the performance of extraction. This data might support future designing of the new CPE applications that are simple and more accurate. We compared CPE with other extraction methods and also showed the advantages and disadvantages of various extraction techniques along with a discussion on their environmental impact. According to the publications reviewed, it is obvious that CPE is an easy, safe, rapid and inexpensive method of extraction. Introduction Determination of pharmaceutical substances in biological matrix is crucial in various fields of medicine and pharmacy, e.g., in pharmacokinetic studies, development of new drugs or in therapeutic drug monitoring [1]. Patients frequently take more than one medication at a time, which may interfere in their individual measurements. There are also large interindividual differences between humans; therefore, the concentration of drug might significantly differ between different individuals. The therapeutic effect of drug depends on its concentration in human plasma; therefore, a proper method of measurement is highly required during the course of treatment. Another problem is the occurrence of relatively low concentrations of drugs in human fluids and tissues, which should be preconcentrated before analysis. Thus, a proper method of sample preparation should be carefully chosen. According to the literature, ~60% of all errors during the entire analytical process are sample preparation [2]. The analyst should consider the physicochemical properties of the compound being examined, such as its chemical nature, polarity, chemical form, as well as the type of the biological material from which the analyte is being isolated. Biological samples are mixtures of different compounds including salts, low-molecular-weight organic compounds and macromolecules, which can interfere with the analysis of the analyte. One of the simplest methods of sample preparation is the removal of proteins by organic solvents or by changing the pH of the sample. However, in many cases, a simple method of preparation is not sufficient for a better analysis. Therefore, various methods of extraction are used during sample preparation. There are several techniques used in the preparation of the sample, but the most popular ones are liquid–liquid extraction (LLE) and solid-phase extraction (SPE). Classical LLE consumes large quantities of organic solvents [2], and SPE is time-consuming and relatively expensive [63]. Therefore, there is an urgent need for a new technique that can be fast, reliable and environment-friendly. Such techniques can yield tangible benefits to the pharmaceutical industry and can lower the price of drugs and provide a cleaner environment. Nowadays, the concept of green chemistry is becoming very popular. One of its principles is to reduce the consumption of organic solvents or to exclude them from the process. Extraction methods such as cloud point extraction (CPE), stir bar sorptive extraction (SBSE), solid-phase microextraction (SPME), single-drop microextraction (SDME) and dispersive liquid–liquid microextraction (DLLME) fulfill this requirement [4–6, 11]. Modern analytical techniques should be simple, ecologically safe, sensitive and selective [59]. Previously, some review articles have already been published on CPE [2, 20, 58–59], but their primary focus was on metal ions as the analytes [20, 58, 59]. Our search yielded only three articles on the extraction of the small organic compounds [2, 56, 57], but only one of them was focused on the extraction of analytes from the human biological matrix [2]. The latter study covers the basic theory of CPE in the analysis of bioactive compounds and was published 10 years ago. Therefore, we aimed to present this review article in order to update our current knowledge regarding the topic of CPE. For instance, risk of matrix effect (ME) is more often coupled with mass spectrometry. Therefore, for the first time, we discuss the effect of the matrix on CPE coupled with liquid chromatography coupled to mass spectrometry (LC–MS/MS). Another novelty of this review is a comparison of the results for the same drug from the same sample extracted by CPE and LLE, as well as assessment of the environmental impact of CPE. We gathered data about CPE from several manuscripts in which CPE was used to isolate pharmaceutical substances from the human biological matrix. We show the most frequently used extraction conditions and provide many examples. The advantages and disadvantages of CPE were compared with other extraction techniques as well. CPE and other extraction techniques Table I presents the list of the advantages and disadvantages of all the described extraction techniques in below paragraph. In the case of LLE, an analyte is extracted from the liquid phase (e.g., blood, plasma, serum and tissue homogenate) into the solvent. The most commonly used solvents are organic solvents such as hexane, chloroform, diethyl ether, dichloromethane, tert-butyl ethyl ether, ethyl acetate and mixtures thereof [3]. LLE is simple and fast, but harmful to the environment due to the usage of organic solvents, which needs to be utilized after use and what influences the final extraction cost. Moreover, there is a risk of incidental inhalation and intoxication of laboratory staff. In addition, residual solvents might have a carcinogenic effect. Compared to other extraction techniques, LLE is cheap and does not need any special laboratory equipment to perform the extraction [3]. LLE can be modified to obtain some significant improvement in the extraction over the original method, but based on the number of published manuscripts, still basic method is most frequently used (Figure 1). One of the modified techniques is supported liquid extraction (SLE), which uses columns filled with inert diatomaceous earth. An aqueous sample is loaded onto the sorbent, where it forms a thin layer. The next step of the process is the extraction of the analyte from the layer with a selected organic solvent. In this type of extraction, sample preparation time is reduced as there is no need for sample shaking. Moreover, SLE can be automated, which positively affects not only the time required for sample preparation but also the reproducibility of the extraction procedure [4, 5]. SLE only differs in that the aqueous solvent is supported in place by a highly polar solid media. Table I The advantages and disadvantages of the described extraction techniques Type of extraction Advantages Disadvantages Citation LLE Quick, universal, cheap, possibilities to analyze complex matrix, good recovery High use of organic solvents, limited selectivity (4,54) SLE Good precision, universal, possibilities of process automatization, low use of organic solvents, possibilities to analyze complex matrix Expensive, requires specific laboratory equipment (4) SDME Low use of organic solvents, possibilities to analyze complex matrix, universal, good recovery, possibilities to analyze complex matrix Few possibilities of method optimization, the risk of drop destroy (5, 6) DLLME Quick, cheap, low use of organic solvents, good recovery, possibilities to analyze complex matrix Limited number of dispersion solution and associated limited possibility of method optimization (4, 7) SPE Low use of organic solvents, large selection of sorbents, universal, possibilities of process automatization and miniaturization, possibilities to analyze complex matrix Poor reproducibility (7, 8) SPME No use of organic solvents, quick, universal, wide range of concentrations, compatible with LC and GC, possibilities to analyze complex matrix Poor reproducibility, brittleness of fiber, poor recovery (8) CPE Quick, cheap, simple, low use of organic solvents, large selection of surfactants, universal, possibilities to analyze complex matrix Impact of ME (1, 2, 10) SBSE Low use of organic solvents, universal, quick, compatible with LC and GC Limited of coatings, requires specific laboratory equipment (9) Type of extraction Advantages Disadvantages Citation LLE Quick, universal, cheap, possibilities to analyze complex matrix, good recovery High use of organic solvents, limited selectivity (4,54) SLE Good precision, universal, possibilities of process automatization, low use of organic solvents, possibilities to analyze complex matrix Expensive, requires specific laboratory equipment (4) SDME Low use of organic solvents, possibilities to analyze complex matrix, universal, good recovery, possibilities to analyze complex matrix Few possibilities of method optimization, the risk of drop destroy (5, 6) DLLME Quick, cheap, low use of organic solvents, good recovery, possibilities to analyze complex matrix Limited number of dispersion solution and associated limited possibility of method optimization (4, 7) SPE Low use of organic solvents, large selection of sorbents, universal, possibilities of process automatization and miniaturization, possibilities to analyze complex matrix Poor reproducibility (7, 8) SPME No use of organic solvents, quick, universal, wide range of concentrations, compatible with LC and GC, possibilities to analyze complex matrix Poor reproducibility, brittleness of fiber, poor recovery (8) CPE Quick, cheap, simple, low use of organic solvents, large selection of surfactants, universal, possibilities to analyze complex matrix Impact of ME (1, 2, 10) SBSE Low use of organic solvents, universal, quick, compatible with LC and GC Limited of coatings, requires specific laboratory equipment (9) Open in new tab Table I The advantages and disadvantages of the described extraction techniques Type of extraction Advantages Disadvantages Citation LLE Quick, universal, cheap, possibilities to analyze complex matrix, good recovery High use of organic solvents, limited selectivity (4,54) SLE Good precision, universal, possibilities of process automatization, low use of organic solvents, possibilities to analyze complex matrix Expensive, requires specific laboratory equipment (4) SDME Low use of organic solvents, possibilities to analyze complex matrix, universal, good recovery, possibilities to analyze complex matrix Few possibilities of method optimization, the risk of drop destroy (5, 6) DLLME Quick, cheap, low use of organic solvents, good recovery, possibilities to analyze complex matrix Limited number of dispersion solution and associated limited possibility of method optimization (4, 7) SPE Low use of organic solvents, large selection of sorbents, universal, possibilities of process automatization and miniaturization, possibilities to analyze complex matrix Poor reproducibility (7, 8) SPME No use of organic solvents, quick, universal, wide range of concentrations, compatible with LC and GC, possibilities to analyze complex matrix Poor reproducibility, brittleness of fiber, poor recovery (8) CPE Quick, cheap, simple, low use of organic solvents, large selection of surfactants, universal, possibilities to analyze complex matrix Impact of ME (1, 2, 10) SBSE Low use of organic solvents, universal, quick, compatible with LC and GC Limited of coatings, requires specific laboratory equipment (9) Type of extraction Advantages Disadvantages Citation LLE Quick, universal, cheap, possibilities to analyze complex matrix, good recovery High use of organic solvents, limited selectivity (4,54) SLE Good precision, universal, possibilities of process automatization, low use of organic solvents, possibilities to analyze complex matrix Expensive, requires specific laboratory equipment (4) SDME Low use of organic solvents, possibilities to analyze complex matrix, universal, good recovery, possibilities to analyze complex matrix Few possibilities of method optimization, the risk of drop destroy (5, 6) DLLME Quick, cheap, low use of organic solvents, good recovery, possibilities to analyze complex matrix Limited number of dispersion solution and associated limited possibility of method optimization (4, 7) SPE Low use of organic solvents, large selection of sorbents, universal, possibilities of process automatization and miniaturization, possibilities to analyze complex matrix Poor reproducibility (7, 8) SPME No use of organic solvents, quick, universal, wide range of concentrations, compatible with LC and GC, possibilities to analyze complex matrix Poor reproducibility, brittleness of fiber, poor recovery (8) CPE Quick, cheap, simple, low use of organic solvents, large selection of surfactants, universal, possibilities to analyze complex matrix Impact of ME (1, 2, 10) SBSE Low use of organic solvents, universal, quick, compatible with LC and GC Limited of coatings, requires specific laboratory equipment (9) Open in new tab Figure 1 Open in new tabDownload slide Number of articles published in the years 2011–2015 with defined search criteria’s; search in PubMed database was based on the keywords: name of the extraction technique + ``drugs” or ``pharmaceutical”. Figure 1 Open in new tabDownload slide Number of articles published in the years 2011–2015 with defined search criteria’s; search in PubMed database was based on the keywords: name of the extraction technique + ``drugs” or ``pharmaceutical”. The other modified LLE is the SDME. This technique is based on the separation between the aqueous phase containing the analyte and the drop of extraction reagent placed on the tip of the needle. This method requires higher solubility of the compound in the solvent than in the sample. A drop of solvent can be immersed directly in the solution or above its surface (in case of extraction of volatile compounds). When the equilibrium is attained, the drop is drawn back into the syringe, where it can be injected directly to the dispenser chromatography or be evaporated and reconstituted in another solvent. SDME significantly reduces the consumption of solvents [6]. The next modified LLE is the DLLME. In this method, two solutions are used. One of them is used for the dispersion of the liquid sample and the other for the extraction (the most commonly used solvents are acetone as disperser solvent and tetrachloroethene as the extraction solvent). The liquid dispersant is used to increase the contact surface between the solvent used in the process of extraction and the aqueous phase. This helps to quickly reach the equilibrium, which increases the performance of the extraction. However, an important issue of the DLLME procedure is the selection of extraction solvent, which should be able to isolate the selected compound with satisfactory recovery. The process itself involves the rapid injection of the two solutions into an aqueous sample containing the analyte and then separating the phases by centrifugation. This method shows high recovery and is fast and simple with good performance and the need for only a small amount of solvent for extraction [7]. One of the advantages of DDLME over SLE is a very low use of solvents and efficiency of extraction not relates to time of extraction. Another type of modified LLE is CPE. This technique is based on the fact that low concentrations of the surfactant above the critical micelle concentration (CMC) can exist as a homogeneous isotropic liquid, which separates into two isotropic phases containing a surfactant in different concentrations. In the surfactant micelle-rich phase, hydrophobic organic components present in the sample are concentrated and separated from more hydrophilic compounds [2]. CPE is a simple, safe and environment-friendly technique, which does not require organic solvents or expensive equipment for the sample preparation. Because CPE is based on surfactants, it is nontoxic to humans and is inexpensive to dispose of [1]. Thus, CPE has many advantages over the standard LLE. Compared to SPE, CPE does not require long hours of optimization and does not need special laboratory equipment. SPE, another type of extraction method, uses disposable columns filled with sorbents. The type of sorbent is selected depending on the chemical properties of the analyte. There were used hydrophilic–lipophilic balanced sorbents, which can be successfully used with ion exchange groups in the multiple analyses of compounds of different polarity [8]. The most commonly used sorbents are modified silica gels and polymer sorbents working on the reverse, normal, ion exchange or mixed modes [8]. SPE columns are convenient to use and are easy to dispose of. The biggest development and increased interest in SPE took place in the 80s and 90s of the 20th century. The development and optimization of this technique is time-consuming. It may become also more time-consuming and expensive when there is a need for a large number of samples to be analyzed in a pharmacokinetic study [8]. However, if automated or manifold approaches are used, then SPE can have high sample throughput. Other methods of extraction based on the mechanism similar to the SPE are available in the literature. One of them is SPME. SPME might be performed without the use of organic solvents. If a solvent has to be used, then their quantity needed is much lower than that needed in LLE and conventional SPE procedures. In SPME, silica fiber coated with a suitable stationary phase (polymeric coating—sorbent) is more commonly used. There are many commercially available SPME fiber coatings that are combinations of polydimethylsiloxane, divinylbenzene, carboxen, polyacrylate and polyethylene glycol. It is a universal technique and is used in the isolation of volatile, medium-volatile and nonvolatile compounds, both organic and inorganic nature. In SPME, sampling, extraction, the concentration of the analyte, as well as the introduction of the sample into the gas chromatograph and liquid chromatograph can be simultaneously achieved [7]. The primary disadvantage of this type of extraction is low absolute recovery, but relative recovery is enough for analytical procedures. Absolute recovery is the % amount of drug recovered from the matrix (e.g., biological fluid) versus the standard (unextracted). The relative recovery is the % amount of drug recovered from the matrix with reference to the extracted standard (standard spiked into the same matrix) [62]. SBSE, another type of extraction, is based on the absorption of the compound on the sorbent layer coated with the movable element placed in the sample. The separation takes place until the equilibrium is achieved between the solution and the sorbent. The compound is desorbed from the sorbent using temperature or a suitable solvent, depending on further analytical procedures [9]. SBSE is an environment-friendly technique. Statistics on selected extraction techniques usage It is very hard to determine how widely a particular method is used. In order to compare the popularity of the selected extraction techniques, we searched the literature using the PubMed database. We limited our search to the years 2011–2015. The search was based on the keywords: name of the extraction technique + ``drugs” or ``pharmaceutical” and date. However, our results could not show real popularity of methods, as what are described in the literature are research articles, while routine analysis rarely gets published. According to the search results, LLE was the most frequently reported method of extraction of pharmaceuticals from biological matrices, SPE was the second and SPME was the third most commonly used modern method of extraction. The growing interest in new methods of extraction was evident during the last years. According to the search results, in 2005, there were only 4 papers published on CPE, and in 2014, there were 58 publications (Figures 1 and 2). Figure 2 Open in new tabDownload slide Percentage of published articles in the years 2011–2015 with defined search criteria’s; search in PubMed database was based on the keywords: name of the extraction technique + ``drugs” or pharmaceutical”. Figure 2 Open in new tabDownload slide Percentage of published articles in the years 2011–2015 with defined search criteria’s; search in PubMed database was based on the keywords: name of the extraction technique + ``drugs” or pharmaceutical”. Concepts and basic theory of CPE The literature describes the use of CPE in the determination of drugs in biological fluids such as plasma, serum or blood [21–39]. It is based on the fact that surfactant at low concentrations above the CMC can exist as a homogeneous isotropic liquid phase (Figure 3), which above the cloud point temperature (CPT) separates into two isotropic phases, both of which contain the surfactant but at different concentrations. Above this temperature, the molecules of surfactants become turbid, thereby creating an aggregate (a micelle) (Figure 3) that orientates its hydrocarbon tails toward the center to create a nonpolar core. Figure 4 presents the diagram of the CPE procedure. A similar effect as CPT can be achieved with the use of ultrasonic energy. The ultrasonic energy might accelerate the reaction and clouding phenomena but requires additional laboratory equipment [12]. The isolated hydrophobic analyte (a large number of bioactive compounds) present in the aqueous solution is favorably partitioned in the hydrophobic core of the micelle formed by nonionic surfactant [2]. Figure 3 Open in new tabDownload slide Surfactant molecule before (A) and after (B) the CMC. Figure 3 Open in new tabDownload slide Surfactant molecule before (A) and after (B) the CMC. Figure 4 Open in new tabDownload slide CPE: 1, analyte; 2, micelle with analyte; 3, water phase; 4, surfactant-rich phase. Figure 4 Open in new tabDownload slide CPE: 1, analyte; 2, micelle with analyte; 3, water phase; 4, surfactant-rich phase. Table II Comparison of toxicity of selected surfactants and extraction solvents Substance EC 50/48 h for D. magna [mg mL−1] LC50/96 h for fish [mg mL−1] Threshold limit algae species: Selenastrum capricornutum green algae[mg mL−1/h] LD50 for rat [mg/kg] Citation Triton X-110 18–26 4–8.9 10 2,000 (17) Triton X-114 6.88 1–10 6.5 1,800 (17) Genapol X-080 7.07 1–10 1.6 2,000 (17) Ethyl acetate 717 230 2000 10.2 (18) Hexane 21.85 4 9.29 16 (18) Methylene chloride 168.2 193 1450 1,600 (18) Tert-butyl ethyl ether 472–681 100 491 4 (18) Substance EC 50/48 h for D. magna [mg mL−1] LC50/96 h for fish [mg mL−1] Threshold limit algae species: Selenastrum capricornutum green algae[mg mL−1/h] LD50 for rat [mg/kg] Citation Triton X-110 18–26 4–8.9 10 2,000 (17) Triton X-114 6.88 1–10 6.5 1,800 (17) Genapol X-080 7.07 1–10 1.6 2,000 (17) Ethyl acetate 717 230 2000 10.2 (18) Hexane 21.85 4 9.29 16 (18) Methylene chloride 168.2 193 1450 1,600 (18) Tert-butyl ethyl ether 472–681 100 491 4 (18) Open in new tab Table II Comparison of toxicity of selected surfactants and extraction solvents Substance EC 50/48 h for D. magna [mg mL−1] LC50/96 h for fish [mg mL−1] Threshold limit algae species: Selenastrum capricornutum green algae[mg mL−1/h] LD50 for rat [mg/kg] Citation Triton X-110 18–26 4–8.9 10 2,000 (17) Triton X-114 6.88 1–10 6.5 1,800 (17) Genapol X-080 7.07 1–10 1.6 2,000 (17) Ethyl acetate 717 230 2000 10.2 (18) Hexane 21.85 4 9.29 16 (18) Methylene chloride 168.2 193 1450 1,600 (18) Tert-butyl ethyl ether 472–681 100 491 4 (18) Substance EC 50/48 h for D. magna [mg mL−1] LC50/96 h for fish [mg mL−1] Threshold limit algae species: Selenastrum capricornutum green algae[mg mL−1/h] LD50 for rat [mg/kg] Citation Triton X-110 18–26 4–8.9 10 2,000 (17) Triton X-114 6.88 1–10 6.5 1,800 (17) Genapol X-080 7.07 1–10 1.6 2,000 (17) Ethyl acetate 717 230 2000 10.2 (18) Hexane 21.85 4 9.29 16 (18) Methylene chloride 168.2 193 1450 1,600 (18) Tert-butyl ethyl ether 472–681 100 491 4 (18) Open in new tab The phase separation might be accelerated by the process of centrifugation. This technique involves several stages. The critical step during CPE is phase separation, which is most frequently achieved by the process of decantation (separating the surfactant-rich phase from aqueous phase). Cooling the sample at −20°C for 20 min before decantation can improve the process [10]. As long as nothing restricts the volume changes that occur during phase change, then the process will be isobaric (constant pressure). In fact, the heat of phase change is slightly different depending on whether the process takes place at constant pressure or constant volume. Before injecting the extracted sample into the instrument, the micelle-rich phase should be suitably prepared, as it will be viscous and cannot be injected directly into the instrument. It should be diluted with an aqueous or organic solvent. In most cases, it is not necessary to clean up the extracted sample before chromatographic determination. CPE involves some manual steps and requires some standard glassware and equipment found in most laboratories. The surfactants are inexpensive and have low flammability. MPCE, a modified CPE, was used in the extraction of dyes such as rhodamine. In this technique, sodium sulfate is used to reduce the cloud point and to eliminate the boiling step. Ultraviolet-visible (UV-VIS) spectrometry is used to detect the dye in a sample volume of 10 μL [13]. Ultrasonic-thermostatic-assisted CPE (UTA-CPE) is another modified method of CPE, where the sample is boiled in an ultrasonic water bath [46]. This reduces the temperature of extraction and time of boiling and lowers the consumption of reagents [14]. Cold column trapping-CPE (CCT-CPE) is another technique in which the phase separation is accelerated and centrifugation is eliminated due to the use of column with the sorbent [47]. The sample is introduced into the system and then the column is cooled. In the next step, the surfactant-rich phase is eluted by the use of solvent [15]. Impact of surfactants and extracting solvents on environmental safety There are some doubts regarding the environmental effect of surfactants, especially on the aquatic environment. According to the available data, surfactants are biodegradable in wastewater treatment plants [16]. Their harmful effect is related mainly to foaming, which reduces the amount of oxygen in the water. Nonionic surfactants are more toxic than the anionic surfactants [17]. Comparing EC 50/48 h (the effective concentration of a substance that causes 50% of the maximum response after exposure for 48 h) of Triton X-114 and the commonly used solvent in LLE, ethyl acetate, for Daphnia magna, the toxicity of Triton X-114 is about 25 times higher (see Table II). However, in CPE, the most commonly used concentration of Triton X-114 is 1–9% [25–39]. About 20–50 mg of Triton X-114 is frequently used in the final volume of 1 mL of sample. In conventional LLE, the volume of solvent used is higher, usually in the range of 6–24 mL [49, 50, 53], which means more than 6,000 mg of solvent is used. Therefore, the solvent might cause more harm to the environmental. It is noteworthy that surfactants are less toxic to humans than that of organic solvents. Based on their toxicity, solvents can be classified into three classes: Class 1 solvents are the most toxic/hazardous. According to the ICH guideline Q3C (R6) on impurities, solvents belonging to Class 1 (e.g., benzene and 1,2-dichloroethane) should not be used in the manufacture of drugs, excipients and drug products because of their unacceptable toxicity or due to deleterious environmental effect [18]. Furthermore, they can have carcinogenic effects. Class 2 solvents (e.g., toluene, acetonitrile and hexane) should be limited in the pharmaceutical products because of their inherent toxicity [18]. Most of the commonly used residual solvents in LLE are classified as Class 2 solvents. Class 3 solvents (e.g., acetone and ethyl acetate) are considered the least toxic/hazardous solvents. These solvents are in general volatile and can cause accidental poisoning due to inhalation, especially during solvent evaporation. Main factors affecting CPE efficiency Effect of the surfactant type and its concentration There are three types of surface-active agents that may be used in CPE: nonionic (e.g., polyglycerol alkyl ethers tweens and others), double ionic (zwitterionic) and anionic surfactants (e.g., alkylbenzene sulfonates). Recently, nonionic surfactants are used more frequently than the other. As a general principle, CPE is more efficient with the use of nonionic surfactants, when more hydrophobic surfactants and more hydrophobic analytes are used [2]. As shown in Table IV, with an increase in the value of logP, the recovery of sulfonamide also increased (correlation r2 = 0.8391). The hydrophobicity of some molecules is pH dependent. Thus, the recovery could be enhanced by the selection of appropriate pH in case of ionizable compounds and/or by the addition of salt, which decreases the solubility of the analyte in the aqueous phase. Every surfactant has some property, which is named as CMC, the concentration at which surfactants begin to form micelle [19]. Above the cloud point (temperature at which phase separation behavior occurs), the single isotropic micelle phase separates into two isotropic phases: first, the aqueous phase that contains the surfactant at a concentration close to the CMC and the second, the surfactant-rich phase, whose volume is very small [20]. CMC depends on the structure of the surfactant. With an increase in the number of carbon atoms in the alkyl chain (i.e., ``tail”) and nonpolar structures in the hydrophilic head, CMC decreases [19]. In the ionic surfactants, CMC depends on the type of counter-ion (usually halide), attached to the hydrophilic part [19]. Triton X-114 is the most frequently used surfactant for CPE of drugs. Other surfactants that are often used are Triton X-100 and Genapol X-080 (Table III). The main advantage of Triton X-114 is its low CPT (23°C), low UV absorbance and high density, which facilitates the phase separation by centrifugation [21]. The increasing concentration of the surfactant improves the recovery, but above a certain point, it dilutes the compound of interest and decreases the preconcentration rate [21]. The concentration of the surfactant should also be carefully selected. This parameter depends on the type of surfactant used. According to the literature, recovery of the analyte increases with the surfactant’s concentration in the range of 1–9%. In the higher concentration, recovery is still high but the dilution of the analyte increases. Surfactants are most commonly used at a concentration of 4% (Table IV). Table III Comparison of most commonly used surfactants Surfactant Formula CPT Density [g/cm3] CMC (20–25°C) [mM] Trition X-114 23°C 1.052 0.2 n = 7–8 Trition X-100 66°C 1.07 0.2–0.9 n = 9–10 Genapol X-080 75.5°C 0.98 0.06–0.15 n = 8–9 Surfactant Formula CPT Density [g/cm3] CMC (20–25°C) [mM] Trition X-114 23°C 1.052 0.2 n = 7–8 Trition X-100 66°C 1.07 0.2–0.9 n = 9–10 Genapol X-080 75.5°C 0.98 0.06–0.15 n = 8–9 Open in new tab Table III Comparison of most commonly used surfactants Surfactant Formula CPT Density [g/cm3] CMC (20–25°C) [mM] Trition X-114 23°C 1.052 0.2 n = 7–8 Trition X-100 66°C 1.07 0.2–0.9 n = 9–10 Genapol X-080 75.5°C 0.98 0.06–0.15 n = 8–9 Surfactant Formula CPT Density [g/cm3] CMC (20–25°C) [mM] Trition X-114 23°C 1.052 0.2 n = 7–8 Trition X-100 66°C 1.07 0.2–0.9 n = 9–10 Genapol X-080 75.5°C 0.98 0.06–0.15 n = 8–9 Open in new tab Table IV Data concerning parameters of CPE procedure in various publications Analyte Surfactant Surfactant final Concentration Recovery logP Temperature Used salt concentration range Used salt con centration (final) Detection type Citation Larotaxel Triton X-114 4.4% 92–94% 1.99 45°C -f -f CPE/HPLC/UV spectrophotometrya (25) Isoniazid Triton X-100 9% 82–84% −0.7 70°C 10–25% NaCl 20% HPLC/UV spectrophotometrya (26) Ofloxacin PONPE 7.5 4.0% 97% −0.39 25°C 4–10% NaCl 6% CPE/FLb (31) Gatifloxacin SDS 4.0% 99% 2.6 25°C 4–10% NaCl 6% CPE/FLb Memantine Triton X-114 1.5% 91–101% 3.28 50°C -f -f CPE/LC/MSc (22) Flurbiprofen Genapol X-080 3.3% 84% 4.2 50°C -f -f CPE/HPLC/UV spectrophotometrya (27) Meloxicam Triton X-114 2.5% 92% 0.1 35°C 5–10% NaCl 5% CPE/HPLC/UV spectrophotometrya (28) Venlafaxine Triton X-114 2.2% 89% 0.43 40°C 0–10% NaCl 6% CPE/HPLC/FLb (32) Arbidol Triton X-114 4% 90% 5.32 45°C -f -f CPE/HPLC/UV spectrophotometrya (21) Paracetamol Triton X-114 3.3% 84% 0.31 25°C 2–5% Na2SO4 2% CPE/FLb (54) Sulfafurazole Triton X-100 5.5% 93% 1.58 -f -f -f CPE/HPLC/UV spectrophotometrya (33) Sulfachloropyridazine 73% 1.36 Sulfamonomethoxine sodium 84% 1.56 Sulfamethoxazole 90% 1.58 Sulfamethoxypyridazine 67% 1.01 Sulfaquinoxaline 96% 1.7 Sulfadimethoxine 97% 1.56 Bisoprolol Triton X-114 2.1% 61% 2.3 55°C -f -f CPE/LC–MSc (1) Antazoline Triton X-114 2.5% - 2.88 40°C -f -f CPE/LC–MSc (10) Abacavir Triton X-114 0.8% 90% 1.20 -f -f -f UFLC-ESI-MS/MSc (36) Efavirenz 0.8% 105% 4.6 Lamivudine 0.8% 82% −1.4 Nelfinavir 0.8% 98% 4.61 Andrographolide Triton X-114 3.3% 81% 2.9 60°C 1–5% NaCl 3% CPE/HPLC/UV spectrophotometrya (35) Dehydroandrographolide 84% 1.78 Pericyazine Triton X-100 4.8% 95% 8.76 60°C 2–6% 4% CPE/HPLC/UV spectrophotometrya (29) Chlorpromazine Triton X-114 4.8% 87% 9.35 Fluphenazine PONPE 3.2% 85% 7.9 Triptonide Triton X-114 1.0% 96% 0.7 55°C -f -f UV spectrophotometrya combined with MEKCe (39) Terazosin PONPE 7.5 0.25% 98% 1.3 20°C 0.5–5% Na2B4O7 2% CPE/FLb (37) Nitrate Triton X-114 0.7% 97% - 45°C 0.2–1.2% (NH4)2SO4 0.8% CPE/HPLC/UV spectrophotometrya (38) Nitrite 99% Triamterene Triton X-114 0.05% 95% 0.98 35°C 0–10% NaCl 2.5% CPE/FLb (30) Paracetamol Triton X-114 7.5% 22% 0.5 -f -f -f RP/HPLC/DADd (2) Promazine 87% 2.5 Chlorpromazine 72% 4.9 Amitriptyline 70% 5.2 Salicyclic acid 59% 2.3 Opipramol 25% 3.4 Alprazolam 61% 2.4 Carbamazepine 36% 2.12 Analyte Surfactant Surfactant final Concentration Recovery logP Temperature Used salt concentration range Used salt con centration (final) Detection type Citation Larotaxel Triton X-114 4.4% 92–94% 1.99 45°C -f -f CPE/HPLC/UV spectrophotometrya (25) Isoniazid Triton X-100 9% 82–84% −0.7 70°C 10–25% NaCl 20% HPLC/UV spectrophotometrya (26) Ofloxacin PONPE 7.5 4.0% 97% −0.39 25°C 4–10% NaCl 6% CPE/FLb (31) Gatifloxacin SDS 4.0% 99% 2.6 25°C 4–10% NaCl 6% CPE/FLb Memantine Triton X-114 1.5% 91–101% 3.28 50°C -f -f CPE/LC/MSc (22) Flurbiprofen Genapol X-080 3.3% 84% 4.2 50°C -f -f CPE/HPLC/UV spectrophotometrya (27) Meloxicam Triton X-114 2.5% 92% 0.1 35°C 5–10% NaCl 5% CPE/HPLC/UV spectrophotometrya (28) Venlafaxine Triton X-114 2.2% 89% 0.43 40°C 0–10% NaCl 6% CPE/HPLC/FLb (32) Arbidol Triton X-114 4% 90% 5.32 45°C -f -f CPE/HPLC/UV spectrophotometrya (21) Paracetamol Triton X-114 3.3% 84% 0.31 25°C 2–5% Na2SO4 2% CPE/FLb (54) Sulfafurazole Triton X-100 5.5% 93% 1.58 -f -f -f CPE/HPLC/UV spectrophotometrya (33) Sulfachloropyridazine 73% 1.36 Sulfamonomethoxine sodium 84% 1.56 Sulfamethoxazole 90% 1.58 Sulfamethoxypyridazine 67% 1.01 Sulfaquinoxaline 96% 1.7 Sulfadimethoxine 97% 1.56 Bisoprolol Triton X-114 2.1% 61% 2.3 55°C -f -f CPE/LC–MSc (1) Antazoline Triton X-114 2.5% - 2.88 40°C -f -f CPE/LC–MSc (10) Abacavir Triton X-114 0.8% 90% 1.20 -f -f -f UFLC-ESI-MS/MSc (36) Efavirenz 0.8% 105% 4.6 Lamivudine 0.8% 82% −1.4 Nelfinavir 0.8% 98% 4.61 Andrographolide Triton X-114 3.3% 81% 2.9 60°C 1–5% NaCl 3% CPE/HPLC/UV spectrophotometrya (35) Dehydroandrographolide 84% 1.78 Pericyazine Triton X-100 4.8% 95% 8.76 60°C 2–6% 4% CPE/HPLC/UV spectrophotometrya (29) Chlorpromazine Triton X-114 4.8% 87% 9.35 Fluphenazine PONPE 3.2% 85% 7.9 Triptonide Triton X-114 1.0% 96% 0.7 55°C -f -f UV spectrophotometrya combined with MEKCe (39) Terazosin PONPE 7.5 0.25% 98% 1.3 20°C 0.5–5% Na2B4O7 2% CPE/FLb (37) Nitrate Triton X-114 0.7% 97% - 45°C 0.2–1.2% (NH4)2SO4 0.8% CPE/HPLC/UV spectrophotometrya (38) Nitrite 99% Triamterene Triton X-114 0.05% 95% 0.98 35°C 0–10% NaCl 2.5% CPE/FLb (30) Paracetamol Triton X-114 7.5% 22% 0.5 -f -f -f RP/HPLC/DADd (2) Promazine 87% 2.5 Chlorpromazine 72% 4.9 Amitriptyline 70% 5.2 Salicyclic acid 59% 2.3 Opipramol 25% 3.4 Alprazolam 61% 2.4 Carbamazepine 36% 2.12 aUV-VIS, ultraviolet-visible bFL, fluorescence spectroscopy cMS, mass spectroscopy dReverse-phase high performance liquid chromatography combined with diode array detector eGC–MEKC, gas chromatography combined with micellar electrokinetic capillary electrophoresis fNo data in the reference Open in new tab Table IV Data concerning parameters of CPE procedure in various publications Analyte Surfactant Surfactant final Concentration Recovery logP Temperature Used salt concentration range Used salt con centration (final) Detection type Citation Larotaxel Triton X-114 4.4% 92–94% 1.99 45°C -f -f CPE/HPLC/UV spectrophotometrya (25) Isoniazid Triton X-100 9% 82–84% −0.7 70°C 10–25% NaCl 20% HPLC/UV spectrophotometrya (26) Ofloxacin PONPE 7.5 4.0% 97% −0.39 25°C 4–10% NaCl 6% CPE/FLb (31) Gatifloxacin SDS 4.0% 99% 2.6 25°C 4–10% NaCl 6% CPE/FLb Memantine Triton X-114 1.5% 91–101% 3.28 50°C -f -f CPE/LC/MSc (22) Flurbiprofen Genapol X-080 3.3% 84% 4.2 50°C -f -f CPE/HPLC/UV spectrophotometrya (27) Meloxicam Triton X-114 2.5% 92% 0.1 35°C 5–10% NaCl 5% CPE/HPLC/UV spectrophotometrya (28) Venlafaxine Triton X-114 2.2% 89% 0.43 40°C 0–10% NaCl 6% CPE/HPLC/FLb (32) Arbidol Triton X-114 4% 90% 5.32 45°C -f -f CPE/HPLC/UV spectrophotometrya (21) Paracetamol Triton X-114 3.3% 84% 0.31 25°C 2–5% Na2SO4 2% CPE/FLb (54) Sulfafurazole Triton X-100 5.5% 93% 1.58 -f -f -f CPE/HPLC/UV spectrophotometrya (33) Sulfachloropyridazine 73% 1.36 Sulfamonomethoxine sodium 84% 1.56 Sulfamethoxazole 90% 1.58 Sulfamethoxypyridazine 67% 1.01 Sulfaquinoxaline 96% 1.7 Sulfadimethoxine 97% 1.56 Bisoprolol Triton X-114 2.1% 61% 2.3 55°C -f -f CPE/LC–MSc (1) Antazoline Triton X-114 2.5% - 2.88 40°C -f -f CPE/LC–MSc (10) Abacavir Triton X-114 0.8% 90% 1.20 -f -f -f UFLC-ESI-MS/MSc (36) Efavirenz 0.8% 105% 4.6 Lamivudine 0.8% 82% −1.4 Nelfinavir 0.8% 98% 4.61 Andrographolide Triton X-114 3.3% 81% 2.9 60°C 1–5% NaCl 3% CPE/HPLC/UV spectrophotometrya (35) Dehydroandrographolide 84% 1.78 Pericyazine Triton X-100 4.8% 95% 8.76 60°C 2–6% 4% CPE/HPLC/UV spectrophotometrya (29) Chlorpromazine Triton X-114 4.8% 87% 9.35 Fluphenazine PONPE 3.2% 85% 7.9 Triptonide Triton X-114 1.0% 96% 0.7 55°C -f -f UV spectrophotometrya combined with MEKCe (39) Terazosin PONPE 7.5 0.25% 98% 1.3 20°C 0.5–5% Na2B4O7 2% CPE/FLb (37) Nitrate Triton X-114 0.7% 97% - 45°C 0.2–1.2% (NH4)2SO4 0.8% CPE/HPLC/UV spectrophotometrya (38) Nitrite 99% Triamterene Triton X-114 0.05% 95% 0.98 35°C 0–10% NaCl 2.5% CPE/FLb (30) Paracetamol Triton X-114 7.5% 22% 0.5 -f -f -f RP/HPLC/DADd (2) Promazine 87% 2.5 Chlorpromazine 72% 4.9 Amitriptyline 70% 5.2 Salicyclic acid 59% 2.3 Opipramol 25% 3.4 Alprazolam 61% 2.4 Carbamazepine 36% 2.12 Analyte Surfactant Surfactant final Concentration Recovery logP Temperature Used salt concentration range Used salt con centration (final) Detection type Citation Larotaxel Triton X-114 4.4% 92–94% 1.99 45°C -f -f CPE/HPLC/UV spectrophotometrya (25) Isoniazid Triton X-100 9% 82–84% −0.7 70°C 10–25% NaCl 20% HPLC/UV spectrophotometrya (26) Ofloxacin PONPE 7.5 4.0% 97% −0.39 25°C 4–10% NaCl 6% CPE/FLb (31) Gatifloxacin SDS 4.0% 99% 2.6 25°C 4–10% NaCl 6% CPE/FLb Memantine Triton X-114 1.5% 91–101% 3.28 50°C -f -f CPE/LC/MSc (22) Flurbiprofen Genapol X-080 3.3% 84% 4.2 50°C -f -f CPE/HPLC/UV spectrophotometrya (27) Meloxicam Triton X-114 2.5% 92% 0.1 35°C 5–10% NaCl 5% CPE/HPLC/UV spectrophotometrya (28) Venlafaxine Triton X-114 2.2% 89% 0.43 40°C 0–10% NaCl 6% CPE/HPLC/FLb (32) Arbidol Triton X-114 4% 90% 5.32 45°C -f -f CPE/HPLC/UV spectrophotometrya (21) Paracetamol Triton X-114 3.3% 84% 0.31 25°C 2–5% Na2SO4 2% CPE/FLb (54) Sulfafurazole Triton X-100 5.5% 93% 1.58 -f -f -f CPE/HPLC/UV spectrophotometrya (33) Sulfachloropyridazine 73% 1.36 Sulfamonomethoxine sodium 84% 1.56 Sulfamethoxazole 90% 1.58 Sulfamethoxypyridazine 67% 1.01 Sulfaquinoxaline 96% 1.7 Sulfadimethoxine 97% 1.56 Bisoprolol Triton X-114 2.1% 61% 2.3 55°C -f -f CPE/LC–MSc (1) Antazoline Triton X-114 2.5% - 2.88 40°C -f -f CPE/LC–MSc (10) Abacavir Triton X-114 0.8% 90% 1.20 -f -f -f UFLC-ESI-MS/MSc (36) Efavirenz 0.8% 105% 4.6 Lamivudine 0.8% 82% −1.4 Nelfinavir 0.8% 98% 4.61 Andrographolide Triton X-114 3.3% 81% 2.9 60°C 1–5% NaCl 3% CPE/HPLC/UV spectrophotometrya (35) Dehydroandrographolide 84% 1.78 Pericyazine Triton X-100 4.8% 95% 8.76 60°C 2–6% 4% CPE/HPLC/UV spectrophotometrya (29) Chlorpromazine Triton X-114 4.8% 87% 9.35 Fluphenazine PONPE 3.2% 85% 7.9 Triptonide Triton X-114 1.0% 96% 0.7 55°C -f -f UV spectrophotometrya combined with MEKCe (39) Terazosin PONPE 7.5 0.25% 98% 1.3 20°C 0.5–5% Na2B4O7 2% CPE/FLb (37) Nitrate Triton X-114 0.7% 97% - 45°C 0.2–1.2% (NH4)2SO4 0.8% CPE/HPLC/UV spectrophotometrya (38) Nitrite 99% Triamterene Triton X-114 0.05% 95% 0.98 35°C 0–10% NaCl 2.5% CPE/FLb (30) Paracetamol Triton X-114 7.5% 22% 0.5 -f -f -f RP/HPLC/DADd (2) Promazine 87% 2.5 Chlorpromazine 72% 4.9 Amitriptyline 70% 5.2 Salicyclic acid 59% 2.3 Opipramol 25% 3.4 Alprazolam 61% 2.4 Carbamazepine 36% 2.12 aUV-VIS, ultraviolet-visible bFL, fluorescence spectroscopy cMS, mass spectroscopy dReverse-phase high performance liquid chromatography combined with diode array detector eGC–MEKC, gas chromatography combined with micellar electrokinetic capillary electrophoresis fNo data in the reference Open in new tab Effect of the temperature The optimal temperature for the CPE is 15–20°C greater than the cloud point of the surfactant. With an increase in the equilibrium temperature, the volume of the surfactant-rich phase decreases due to the disruption of hydrogen bonds and dehydration of the phase [32]. The yield of the extraction process increases with increasing temperature to a point above CPT [22]. CPT is the temperature at which the mixture starts to phase-separate and is specific for every type of surfactant. However, too high temperature may reduce recovery of the analyte due to the decomposition of heat-labile compounds as well as the thermal instability of the surfactant aggregates [25]. Thus, a too high temperature of extraction should not be applied in the analysis of thermo-labile compounds, e.g., some vitamins or metal ions extracted in combination with the chelating agent. Most commonly used temperatures are in the range 40–60°C (Table IV). It is noteworthy that most of the studies have reported the use of Triton X-114 as the surfactant, whose CPT is 23°C. However, there are reports where the temperatures in the range of 35–60°C have been used. Similarly, Triton X-100 has been used in a temperature range of 60–70°C (its CPT is 60°C). The reduction in the temperature of extraction below the ``15–20°C greater than CPT of surfactant” might have been due to the addition of salt, which reduces the CPT of the surfactant (Table IV). Effect of pH Optimization of pH is an important parameter of CPE. Analytes can exist in several forms in solution, depending on the pH of the solution and the chemical composition. The analyte might exist in either charged or in uncharged forms. The ions of the molecule, which are formed on deprotonation of a weak acid or on protonation of a weak base, normally do not interact with the micellar aggregate as strongly as the neutral form. In such a case, maximum extraction efficiency is achieved at pH values where the uncharged form of the analyte prevails, and therefore, the analyte is favored to be partitioned into the micellar phase of nonionic surfactant [27]. If the pH of the sample is not considered during extraction, then there might be a lesser yield of the analyte [22]. This might lead to the poor recovery of the analyte and high or even insufficient limit of detection (LOD). Literature also describes the effective use of ionic surfactants to extract charged analytes using CPE [40]. Clinical investigations, especially toxicological analysis, often require the screening of complex matrices for the presence of potentially toxic compounds [11]. The biological matrices contain complex organic compounds, which differ in physicochemical properties, such as dissociation constants (pKa) or partition coefficients (logP). This affects the extraction process of the chosen analyte from the biological matrix [11]. Sequential CPE, a modification of CPE, gives the possibility to screen biological matrix for the presence of various drugs. Drugs are classified into two groups based on their pH: acidic/neutral compounds (fraction A) from pH 6 and basic compounds (fraction B) from pH 12. Based on those classifications and chemical parameters, chemical substances were extracted in different conditions and can be analyzed. Effect of salt Addition of neutral salts, e.g., NaCl and CaCl2, affects the value of CMC. In the case of the nonionic surfactants, the value of CMC decreases with increasing concentration of the electrolyte [19]. This reduction is significantly higher for ionic surfactants [19]. Use of salts increases the number of aggregates and the size of formed micelles. Moreover, in the case of ionic surfactants, increase in the ionic strength of the solution promotes the separation of the two phases (surfactant-rich phase and aqueous phase), by increasing the density of the water layer [19]. In the case of nonionic surfactants, an increase in the ionic strength of the solution demotes the separation of the two phases. The addition of electrolytes improves the efficiency of the extraction [41], especially for more polar substances. It reduces the CPT and improves the effect of hydrophobic interactions between the surfactant and the analyte [20]. A previous study has validated the effect of the addition of neutral salt (4–10%) on the final recovery of the analyte (Table IV) [28]. Salt in the range of 1–4% caused an increase in the recovery of the analyte by ~10–20%, and in the range of 7–10%, it decreased by ~10–25%. The increased extraction efficiency in the presence of 1–4% of salt was probably due to the salt-out effect, which reduces the amount of water available to dissolve the molecules of the analyte [28]. Too high concentration of salt will competitively carry substances into the protein deposition; this can lower the concentration of drug in the solution and will have impact on recovery [28]. According to the literature, the most commonly used concentration of salt is 4–6% (Table IV). Furthermore, the use of NaCl or Na2SO4 should be carefully considered since they are not compatible with LC–MS/MS technique [4]. Use of these salts could result in high ME and deposition in the source [4]. Impact of surfactant on selection of determination method Surfactants might affect the accuracy and precision of bioanalytical methods, causing an ME [42]. This is especially true for LC–MS/MS. ME is caused when a matrix-dependent weakening or strengthening of the analytical signal is observed [43, 53]. It is suspected to occur due to the co-elution of the analyte and other compounds from the chromatographic column [55]. Interferences compete with the analyte due to the limited access to charge and space on a droplet’s surface [60]. Another possible cause of ME in an electrospray ionization (ESI) source is the increase in viscosity of the liquid phase due to the high concentration of interferences. Moreover, changes in the surface tension of spray droplets may hamper spray forming and reduce the number of ions reaching the detector [61]. The following parameters can get affected due to ME: LOD, limit of quantification, accuracy, linearity and precision of the method. There are two types of MEs: absolute and relative. ``Relative” ME is defined as the comparative studies of various ME-determining parameters such as standard line slope and matrix factor among different lots of same matrices (i.e., plasma to plasma and urine to urine). However, when these parameters are compared using a single lot of matrix, it is termed as ``absolute” ME. Absolute ME was calculated using the formula: $$ {ME}_A=\frac{\mathrm{the}\ \mathrm{peak}\ \mathrm{area}\ \mathrm{of}\ \mathrm{the}\ \mathrm{analyte}\ \mathrm{in}\ \mathrm{the}\ \mathrm{matrix}\ }{\mathrm{the}\ \mathrm{peak}\ \mathrm{area}\ \mathrm{of}\ \mathrm{the}\ \mathrm{analyte}\ \mathrm{in}\ \mathrm{the}\ \mathrm{solvent}}\times 100\%$$ MEA between 85 and 115% was considered as insignificant. MEA below 85% indicates suppression, whereas over 115%—enhancement of the signal. Relative ME (MER) was calculated as a coefficient of variation of the ME for post-extraction spiked samples plasma originating from different lots. MER lower or equal to 15% was considered as insignificant. Determination of ME requires mass spectrometry due to the possibility of changing the ionization of the test compound under the influence of components of biological material, especially the effect of surfactants could be crucial [44, 55]. Surfactants used in CPE might cause significant ME due to interference with droplet’s evaporation and signal suppression. There are some publications where ME was checked for CPE combined with LC–MS detection [1, 10]. In one of them, where antazoline is analyzed in human plasma with the combined method of CPE–LC–MS/MS, the absolute ME was calculated as 135%, relative ME as 12% for lower concentration and the absolute ME as 133% and relative ME as 10% for higher concentration, respectively [10]. In the second publication, where bisoprolol was analyzed in human plasma, the absolute ME was calculated as 98%, relative ME as 11.5% for lower and 4.4% for higher concentration, respectively [1]. Thus, ME was not found to be a limiting factor in the case of the studied drugs. Another study conducted experiments to analyze the level of susceptibility of LC–MS to absolute and relative ME when coupled with CPE in the determination of drugs in human plasma. Seventy-three model drugs with different properties were screened. The authors coined a new term—the surfactant effect to estimate the influence of the surfactant on the ionization of the analyte [55]. When low concentrations of the surfactant (1.5%) was used, the authors observed significant surfactant ME (MES) (effect that were recognized as impact of used surfactant) and absolute ME only for 14% (MES) and 25% (MEA) of the analytes. Most importantly, 14% of the analytes showed significant relative ME when surfactant concentration was lowered from 6–1.5% and 11% of analytes, showed the same when the temperature was reduced from 55–40°C. A unique methodology for the evaluation of ME by combining the experimental results with data processing based on molecular descriptors has been proposed. According to the study, classification trees may be used to select the extraction conditions, which may help to decrease ME with the highest probability [55]. As an example, they showed the correlation that low polar surface area increased the risk of occurrence of absolute ME, especially for the compounds with a shorter retention time [55]. Relative ME could be predicted on the basis of retention time; for the compounds eluting with short retention time, it is rather unexpected. This approach may speed up the developmental process of CPE. Results of their experiment showed that CPE combined with LC–MS is not related to a significant ME in the optimal pH of extraction and the combination of CPE–LC–MS enables the measurement of the analyte in a reliable manner [55]. Surfactants might also interfere with detection methods other than LC–MS/MS [50], but in none of the reviewed publications, ME was analyzed. There are several types of detection methods combined with CPE. Most commonly used detection methods are UV-VIS spectrometry and spectrofluorometry. In most cases, HPLC is used to separate the analyte from the matrix. In UV-VIS-based methods, interferences from surfactant are frequently observed due to its chromospheres (as an example, for Polysorbate 80, the electronic transitions typically take place at or below 300 nm) [45]. These interferences limit the use of a particular surfactant in the method or prompt to use other types of detection methods. Another possible cause of measurement uncertainty is difficulty in pipetting viscous liquids e.g., surfactants, which affects the yield of the compound [1]. Comparison of CPE and LLE methods Literature is lacking with regard to the comparison of CPE and other extraction methods for the determination of drugs in biological matrices. Until 2015, there were not studies compare of CPE and LLE. In 2015 and 2016, two articles were published which compared CPE and LLE [1, 10]. One report described the use of CPE combined with LC/MS in the determination of antazoline in human plasma. Their results showed that these methods are compatible [10]. The average accuracy value between the results of LLE and CPE was 3.3% (standard deviation [SD] = 11%) [10]. Acceptance criterion set by the European Medicines Agency (EMA) is ±20% of the imposed 67% of repetitions, and the percentage accuracy was met for 32 out of 33 samples (97%). Other reports related to bisoprolol showed that the plasma concentrations in the clinical samples obtained by the CPE and LLE methods were comparable in the range of 1.0–70 ng mL−1 [1]. The average accuracy value between the results of LLE and CPE was 3.3% (SD = 11%) [1]. Acceptance criterion set by the EMA was met for 32 out of 33 samples (97%) [4]. It is also notable that in lower concentrations of the analyzed substances, repeatability of CPE is lower than in LLE, 3.6% in comparison with 8.3% [10]. This result confirms that CPE and LLE are compatible. As CPE has been shown to be safer for the environment, it should be used more often for the preparation of the sample. Comparison of CPE efficiency in the reviewed methods Table IV shows the comparison of studies related to the analyses of drugs in the human biological matrix, where CPE was used as a method of sample preparation and extraction. In total, 43 different drugs have been extracted and tested. In general, CPE has shown good recovery of the analytes in the range of 90–100% for 19 drugs, and for 11 drugs, it was 80–90%. Recovery below 80% was observed only for 13 drugs. Higher recovery was obtained for efavirenz, 105%; gatifloxacin, 99%; and terazosin, 98%. In general, when a single analyte was extracted, then there was a good recovery. However, bisoprolol showed only moderate recovery of 46% (relative SD [RSD] = 12%) for higher concentrations (60 ng mL−1) and 61% (RSD = 14%) for lower concentrations (0.9 ng mL−1) [1]. The reason for this might be the lack of extraction salts in the method due to the fear of LC–MS source clogging. Another fact is that good recovery can be obtained even with the use of very small concentrations of surfactants like in the analyses of nelfinavir, efavirenz and abacavir [36], where only 0.8% of the surfactant was used. It is important in the context of the environmental effect (see annex 1.5). However, some researchers apply very high concentrations of surfactant in order to obtain a satisfactory recovery, like in the case of promazine where final concertation of the surfactant was 7.5% and the recovery was 87% [2]. Similarly, the recovery procedure of isoniazid used 9% of the surfactant, which showed an 82–84% recovery [26]. Researchers have also used high concentrations of salt in order to obtain a good recovery of the analyte. For example, in the extraction of ofloxacin and gatifloxacin, 6% of salt was used and 97 and 99% of the analyte was obtained, respectively. Isoniazid was extracted by using a high concentration of salt (20%) to obtain moderate recovery (82–84%). In general, when salts were added, recovery was always above 80%. According to the literature, the most commonly used concentration of salt was 4–6%. However, not all detection methods are compatible for such additives e.g., in MS method, this could result in high ME and deposit in the source [4]. CPE is characterized by a high capacity to preconcentrate analytes of different polarities and molecular weight—in the studied articles described analytes have high molecular weight e.g., larotaxel (831.912 g mol−1) or low molecular weight e.g., meloxicam (138.122 g mol−1). However, the disadvantage of CPE is the need for optimization of the method for all the analytes separately. For example, in the multimethod analysis of compounds with similar structures and properties e.g., pericyazine and chlorpromazine; andrographolide and dehydro-andrographolide; as well as abacavir, efavirenz, lamivudine and nelfinavir, the recoveries were good ranged from 81–105% [29, 35, 36]. However, when the structures were different (e.g., triamterene, paracetamol, promazine, chlorpromazine and amitriptyline), not all substances were extracted with good recovery [30] (95% for triamterene to 22% for paracetamol). Conclusion According to this review, the parameters that affect the outcome of CPE are the type of surfactant and its concentration, pH, the temperature of extraction and the addition of neutral salt. The type surfactant to be used depends on the type of analyte to be extracted. As a general rule, CPE can be more efficient when more hydrophobic surfactants and more hydrophobic analytes are used [2]. Triton X-114 at a concentration of 4% is the most common surfactant that is used. In addition, pH is an important parameter that affects the extraction process. Maximum efficiency can be achieved at pH values where the uncharged form of the analyte prevails, and therefore, the analyte is favored to be partitioned into the micelle phase of nonionic surfactant [27]. Another important parameter of CPE is the temperature of extraction. In general, the temperature of extraction should be 15–20°C greater than the cloud point of the surfactant. Most frequently used temperature is in the range of 40–50°C. Addition of neutral salt in the range 1–4% affects the CMC of surfactant thereby promoting the extraction process. Unfortunately, neutral salts can be used only when the analytical technique used is not LC–MS. It has been shown that both CPE and LLE are compatible techniques [10]. In addition, CPE is less harmful to the environment than that of other types of extraction techniques, especially LLE. Thus, we can conclude that CPE can be widely used in the bioanalysis, due to its simplicity, speed of execution, low impact on the environment and high optimization capability. Nowadays, there is a growing interest among researchers to develop new methods of extraction. 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TI - Cloud Point Extraction in the Determination of Drugs in Biological Matrices
JF - Journal of Chromatographic Science
DO - 10.1093/chromsci/bmz064
DA - 2020-01-23
UR - https://www.deepdyve.com/lp/oxford-university-press/cloud-point-extraction-in-the-determination-of-drugs-in-biological-to0trJcQm0
SP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -